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- PDB-4uj2: Protein Kinase A in complex with an Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4uj2
TitleProtein Kinase A in complex with an Inhibitor
Components
  • CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA
  • CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR COMPLEX / PROTEIN KINASE A
Function / homology
Function and homology information


cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction ...cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cAMP-dependent protein kinase inhibitor activity / cellular response to cold / cAMP-dependent protein kinase / regulation of osteoblast differentiation / Loss of phosphorylation of MECP2 at T308 / cAMP-dependent protein kinase activity / sperm capacitation / CREB1 phosphorylation through the activation of Adenylate Cyclase / negative regulation of glycolytic process through fructose-6-phosphate / PKA activation / ciliary base / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / negative regulation of interleukin-2 production / postsynaptic modulation of chemical synaptic transmission / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / protein kinase A catalytic subunit binding / PKA activation in glucagon signalling / Regulation of MECP2 expression and activity / mesoderm formation / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / DARPP-32 events / regulation of cardiac muscle contraction / regulation of cardiac conduction / sperm flagellum / regulation of macroautophagy / renal water homeostasis / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Hedgehog 'off' state / regulation of proteasomal protein catabolic process / negative regulation of smoothened signaling pathway / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Ion homeostasis / Recruitment of mitotic centrosome proteins and complexes / positive regulation of gluconeogenesis / sperm midpiece / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / regulation of G2/M transition of mitotic cell cycle / cellular response to glucagon stimulus / Anchoring of the basal body to the plasma membrane / calcium channel complex / cellular response to epinephrine stimulus / Mitochondrial protein degradation / protein serine/threonine/tyrosine kinase activity / protein kinase A signaling / protein export from nucleus / CD209 (DC-SIGN) signaling / positive regulation of calcium-mediated signaling / regulation of heart rate / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / Regulation of insulin secretion / cellular response to glucose stimulus / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / neuromuscular junction / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cytokine-mediated signaling pathway / VEGFA-VEGFR2 Pathway / mRNA processing / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / manganese ion binding / Factors involved in megakaryocyte development and platelet production / cellular response to heat / peptidyl-serine phosphorylation / dendritic spine
Similarity search - Function
cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-NVV / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.019 Å
AuthorsAlam, K.A. / Engh, R.A.
CitationJournal: Chemistry / Year: 2016
Title: Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of Pka and a Pkb Mimic.
Authors: Lauber, B.S. / Hardegger, L.A. / Asraful, A.K. / Lund, B.A. / Dumele, O. / Harder, M. / Kuhn, B. / Engh, R.A. / Diederich, F.
History
DepositionApr 7, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 30, 2019Group: Advisory / Data collection ...Advisory / Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / pdbx_unobs_or_zero_occ_atoms
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.2Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.3Jan 10, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA
B: CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5984
Polymers43,0352
Non-polymers5632
Water3,369187
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2380 Å2
ΔGint-2.5 kcal/mol
Surface area15670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.813, 74.746, 79.131
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA / PKA C-ALPHA


Mass: 40808.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Protein/peptide CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA / PKI-ALPHA / CAMP-DEPENDENT PROTEIN KINASE INHIBITOR / MUSCLE/BRAIN ISOFORM


Mass: 2226.411 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 6-25 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P61925
#3: Chemical ChemComp-NVV / 7-[(3S,4R)-4-(3-iodanylphenyl)carbonylpyrrolidin-3-yl]-3H-quinazolin-4-one


Mass: 445.254 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16IN3O2
#4: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 187 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer detailsPHOSPHOSERINE (SEP): PHOSPHORYLATION (4S)-2-METHYL-2,4-PENTANEDIOL (MPD): MPD PHOSPHOTHREONINE (TPO) ...PHOSPHOSERINE (SEP): PHOSPHORYLATION (4S)-2-METHYL-2,4-PENTANEDIOL (MPD): MPD PHOSPHOTHREONINE (TPO): PHOSPHORYLATION

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.47 Å3/Da / Density % sol: 50.15 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 10MG/ML PROTEIN, 25MM BISTRIS/MES PH6.9, 50MM KCL, 1.5MM OCTANOYL-N-METHYLGLUCAMIDE, 1MM PROTEIN KINASE INHIBITOR PEPTIDE, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.02→43.33 Å / Num. obs: 25822 / % possible obs: 90.2 % / Observed criterion σ(I): 2 / Redundancy: 4.01 % / Biso Wilson estimate: 33.7 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 18.33
Reflection shellResolution: 2.02→2.09 Å / Redundancy: 4 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 2.07 / % possible all: 90.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3VQH

3vqh


Resolution: 2.019→43.331 Å / SU ML: 0.22 / σ(F): 1.36 / Phase error: 21.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2092 1996 7.7 %
Rwork0.1615 --
obs0.1652 25817 90.17 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.019→43.331 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2907 0 33 187 3127
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083023
X-RAY DIFFRACTIONf_angle_d1.0294093
X-RAY DIFFRACTIONf_dihedral_angle_d13.8661121
X-RAY DIFFRACTIONf_chiral_restr0.07432
X-RAY DIFFRACTIONf_plane_restr0.004520
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0186-2.06910.31741350.24771690X-RAY DIFFRACTION91
2.0691-2.12510.26641380.21261700X-RAY DIFFRACTION92
2.1251-2.18760.24921570.20031702X-RAY DIFFRACTION93
2.1876-2.25820.25531390.20251724X-RAY DIFFRACTION91
2.2582-2.33890.2191400.17471710X-RAY DIFFRACTION92
2.3389-2.43250.23161430.17291703X-RAY DIFFRACTION92
2.4325-2.54320.22171390.16281729X-RAY DIFFRACTION92
2.5432-2.67730.21681410.16231695X-RAY DIFFRACTION90
2.6773-2.8450.2631490.17141677X-RAY DIFFRACTION90
2.845-3.06460.22121470.16821710X-RAY DIFFRACTION90
3.0646-3.37290.20951370.15981692X-RAY DIFFRACTION89
3.3729-3.86070.18111440.14611692X-RAY DIFFRACTION89
3.8607-4.86310.17291480.13131683X-RAY DIFFRACTION87
4.8631-43.34120.19311390.15961714X-RAY DIFFRACTION84
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.81770.5007-0.27993.10340.29963.9404-0.0102-0.01560.19110.2882-0.1328-0.47110.01010.53160.14470.1594-0.0274-0.01570.48690.02520.408235.162211.46499.0056
25.05590.813-1.37061.57380.77213.8581-0.14980.40590.2116-0.04960.152-0.1054-0.2230.1017-0.00810.2317-0.0246-0.01220.27350.07380.337330.002219.7317-0.0731
30.46640.4951-0.33383.41130.34992.82620.0337-0.07340.2950.05170.0495-0.18490.02690.3945-0.03780.2495-0.0208-0.0380.33710.01090.309229.790812.22489.2678
40.83820.20750.03943.32581.81542.8705-0.08240.18590.0576-0.08920.135-0.09960.22020.3071-0.04990.18330.01950.03810.34680.03090.274328.764.5983-7.3459
51.24950.06420.04131.91041.06362.23620.00760.0934-0.16420.0874-0.0568-0.3040.50770.385-0.0030.25190.10520.01870.30020.04070.256131.183-3.66931.5181
61.19060.0819-0.22741.52391.45783.3939-0.07190.0136-0.00670.2221-0.17610.15460.6299-0.2050.21370.2712-0.03470.05560.2310.02710.216117.2754-4.34864.7428
71.5059-0.31840.12121.08640.11361.9911-0.0314-0.048-0.45890.07670.0711-0.2461.32120.23530.06410.65630.16280.03620.29690.00210.321728.9518-15.26071.0986
80.66980.72480.03232.84220.32062.9107-0.04010.04120.2472-0.09340.1133-0.0955-0.62150.3825-0.09860.2311-0.04-0.0230.33490.06910.412526.185120.4545-1.2289
92.30890.02191.22553.52284.16815.57150.25150.152-0.32730.295-0.2817-0.18460.4534-0.27410.02750.2799-0.00550.02630.33470.02470.25812.7009-8.4527-15.5406
107.82141.0687-1.21383.3338-1.69116.1647-0.0944-0.12140.3010.60660.18670.2683-0.1965-0.268-0.00980.4320.00610.03530.23360.02580.306113.70213.3488-3.9911
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 14 THROUGH 54 )
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 55 THROUGH 81 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 82 THROUGH 114 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 115 THROUGH 139 )
5X-RAY DIFFRACTION5CHAIN 'A' AND (RESID 140 THROUGH 179 )
6X-RAY DIFFRACTION6CHAIN 'A' AND (RESID 180 THROUGH 252 )
7X-RAY DIFFRACTION7CHAIN 'A' AND (RESID 253 THROUGH 316 )
8X-RAY DIFFRACTION8CHAIN 'A' AND (RESID 317 THROUGH 350 )
9X-RAY DIFFRACTION9CHAIN 'B' AND (RESID 5 THROUGH 11 )
10X-RAY DIFFRACTION10CHAIN 'B' AND (RESID 12 THROUGH 24 )

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